As CML treatment strategies are shifting to inducing a strong response in the early phase, it is important to prioritize the use of effective drugs.” Timothy Hughes, Professor of Hematology at the South Australian Health and Medical Research Institute, recently gave this assessment regarding CML treatment strategies during an interview with Dailypharm.

The development of various tyrosine kinase inhibitors (TKIs), starting with Novartis' Gleevec, a first-generation targeted anticancer drug, in 2006, then the second-generation treatment options BMS' Sprycel, Novartis' Tasigna, Pfizer’s Bosulif, Il-Yang Pharmaceutical’s Supect, and the third-generation TKI Otsuka's Iclusig, has dramatically improved survival rates.

However, since the existing first- to third-generation TKIs target the ATP binding site, there is a high possibility of developing resistance to mutations, which limits long-term treatment sustainability.

In addition, as treatment options are limited for patients at risk of cardiovascular disease, there is a need for effective switching strategies and new treatment options in the third-line treatment space.

Unlike existing treatment options, the fourth-generation TKI Scemblix is approved and mainly used as a third-line treatment for CML in Korea due to its specifically targeting the ABL myristoyl pocket t (STAMP) inhibition mechanism.

Recently, it has been approved as a first-line treatment in Korea, the United States, and Europe, expanding its scope of use.

Professor Hughes said, “We have seen a dramatic improvement in survival since the advent of TKI-based treatments, but many patients still experience treatment failure due to drug intolerance or resistance.” He added, “In particular, Scemblix is becoming an important alternative for patients who were contraindicated from using existing TKI treatment due to cardiovascular disease, etc.” Scemblix demonstrates superior efficacy in direct comparison studies with existing targeted therapies Scemblix has demonstrated its therapeutic improvement effect through a head-to-head study with existing targeted therapies.

The clinical trial, ASC4FIRST, was the first study to compare Scemblix with standard first-line treatments currently available for newly diagnosed CML patients.

The trial randomly assigned adult CML patients to the Scemblix group and the standard TKI treatment group and compared the major molecular response (MMR) rate at week 48.

The results of the study showed that the MMR achievement rate at week 48 was 67.7% in the Scemblix-treated group and 49.0% in the standard TKI-treated group, showing an 18.9% difference.

In terms of safety, the Scemblix-treated group showed a relatively low incidence of Grade 3 or higher adverse reactions, discontinuation rate due to adverse reactions, and dose adjustment and discontinuation rate for adverse reaction management compared to the control group.

The biggest concern for TKI treatments, including Iclusig, which had been mainly used as a third-line therapy, was cardiovascular toxicity.

Iclusig is known to have a tendency to increase the incidence of arterial occlusion depending on the dose.

According to Professor Hughes, Iclusig should be used only in patients with no other treatment option because there have been many serious arterial system adverse reactions observed even at the standard dose of 45 mg per day.

STAMP inhibitors have high target specificity as they act on the myristoyl pocket of the BCR-ABL1 protein, not the ATP binding site.

Through this differentiated mechanism of action, Scemblix offers the advantage of maintaining a strong therapeutic effect while minimizing side effects.

Professor Hughes commented, “Through the ASC4FIRST trial, Scemblix has demonstrated both efficacy and safety profiles superior to those of Gleevec, Tasigna, and Sprycel, which are currently used as first-line treatments for CML.” He went on to say, “In particular, Scemblix showed a higher MMR compared to Gleevec and also showed excellent results in terms of safety.

The treatment discontinuation rate due to toxicity was also only half that of Gleevec.

In addition, Scemblix also demonstrated higher treatment response rates and safety in the patient group compared to second-generation TKIs.” Potential rises for Scemblix as a first-line treatment option...

“One step closer to treatment-free remission” #EB Professor Hughes believes that while CML treatment strategies have focused on improving survival in the past, it is now important to enable patients to achieve treatment-free remission and enjoy a 'life without need for treatment.' According to Professor Hughes, recent CML treatments tend to focus on inducing a strong response early, in the first-line treatment phase.

This is because a fast and strong response induced by intensive treatment from the beginning can lead to a positive prognosis in the long term and ultimately increase the likelihood of achieving a treatment-free remission.

Professor Hughes said, “Another notable agenda is that the treatment goal of patients is shifting to treatment-free remission.

In fact, when patients are asked what treatment goal they most desire, most of them want to ‘no longer take medication.’ To date, the proportion of patients who have reached treatment-free remission is about 30%, but we expect that the figure will rise to more than 50% in the future through the use of STAMP inhibitors.” Professor Hughes believes that Scemblix has a high potential for use as a first-line treatment for CML.

The ASCEND study, led by Professor Hughes, was the first Scemblix monotherapy clinical trial, involving approximately 100 patients.

Professor Hughes explained that the results of the study were similar to those of the pivotal Scemblix clinical trial.

“In Australia, ASCEND is currently undergoing a follow-up clinical trial.

Patients who meet the criteria for participation are mostly enrolled in the study and receiving Scemblix as a first-line treatment,” added Professor Hughes.

“For patients who are unable to participate in the trial, we are treating them with the best available option.” He went on to say, “Currently, the most important goal of first-line treatment is for patients to achieve a deep molecular response early and ultimately achieve a treatment-free remission.

However, for patients who need to receive third line of treatment, the treatment goals will inevitably vary depending on the course and situation.” He said, “Scemblix has shown high safety and efficacy from the early stages of clinical trials.

It is a drug that has shown the potential to be used not only as third-line treatment but also as first-line treatment.” He also emphasized, “We expect a strong therapeutic effect when Scemblix is used as a first-line treatment.

If there were no restrictions set in our clinical trials, more than 90% of the patients may use Scemblix as a first-line treatment.”